Mechanisms Of Cell Death: Apoptosis, Necroptosis, And Pyroptosis (Bertheloot et al., 2021)

Описание: Cell death is a fundamental physiological process essential for embryonic development, organ maintenance, and immunity. While scientists traditionally viewed cell death as a simple dichotomy between uncontrolled necrosis and regulated apoptosis, recent research reveals a complex landscape of interconnected pathways. This video explores the three best-understood modalities of programmed cell death: apoptosis, necroptosis, and pyroptosis.

I. The Evolution Of Cell Death Research
Cell death plays a vital role in immune selection and development.
Billions of cells die daily and are cleared by phagocytes.
Sudden cell death can release danger signals called DAMPs.
Early research divided death into necrosis and apoptosis.
New studies reveal intricate connections between death pathways.
These processes determine how dying cells affect their surroundings.

II. Necroptosis: Regulated Necrosis
This is a pro-inflammatory form of regulated cell death.
It was evolved to detect pathogens and promote tissue repair.
Activation occurs via receptors like TNFR1 and Toll-like receptors.
Key signaling proteins include RIPK1 and RIPK3.
The protein MLKL forms the necrosome complex with RIPK3.
MLKL translocates to the membrane to form pores.
This pore formation leads to cell swelling and rupture.
It releases cytokines and alarmins into the extracellular space.
Viral inhibitors often target this pathway to aid replication.
Necroptosis is implicated in ischemia-reperfusion injuries.

III. Pyroptosis: A Master Regulator Of Inflammation
Pyroptosis is a highly inflammatory type of cell death.
It is triggered by sensors known as inflammasomes.
Common sensors include NLRP3, AIM2, and Pyrin.
These sensors detect pathogen and damage-associated patterns.
Activation leads to the formation of ASC specks.
Caspase-1 is activated to process cytokines IL-1beta and IL-18.
Gasdermin D is cleaved to form large membrane pores.
This causes a ballooning effect and eventual cell lysis.
It eliminates intracellular niches for pathogen replication.
Dysregulation is linked to Alzheimer's and metabolic diseases.

IV. Apoptosis: The Silent Executioner
Apoptosis is a conserved mechanism of regulated cell death.
It was long thought to be the only regulated death pathway.
The intrinsic pathway involves mitochondrial permeabilization.
The extrinsic pathway is triggered by cell surface death receptors.
Proteins of the BCL-2 family regulate the mitochondrial release.
Caspase-9 initiates the intrinsic caspase cascade.
Caspase-8 and Caspase-10 initiate the extrinsic pathway.
Executioner Caspase-3 and Caspase-7 dismantle the cell.
It results in membrane blebbing and DNA fragmentation.
Apoptotic cells release metabolites to aid tissue repair.

V. Cross-Talk And Regulation
Cell death pathways are not isolated but highly interconnected.
Caspase-8 acts as a molecular switch between pathways.
It suppresses necroptosis to favor apoptosis.
Pathogens have evolved to block specific death pathways.
Viruses like CMV express proteins to inhibit BAX and BAK.
The PANoptosome complex integrates multiple death signals.
This complex triggers pyroptosis, apoptosis, and necroptosis.
The cellular context determines which pathway is executed.

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Source:
Bertheloot, D., Latz, E., & Franklin, B. S. (2021). Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cellular & Molecular Immunology, 18, 1106–1121. https://doi.org/10.1038/s41423-020-00...

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